tbuckley/cabot-search huggingface dataset:
ATRT-18. ELUCIDATING THE ETMR MICROENVIRONMENT USING SPATIAL MULTI-OMICS TECHNOLOGIES
Authors: Evangelos Liapis, Annapurna Pamreddy, Kelly O’Neill, Allison Maas, Derek Hanson, Claire Carter
Journal: Neuro-Oncology (2023)

Abstract Embryonal tumor with multilayered rosettes (ETMR) is a highly aggressive CNS neoplasm that occurs almost exclusively in infants under 4 years of age and is associated with an extremely poor prognosis. A bottleneck in the development of new and curative treatments for ETMR stems from our limited understanding of the spatiotemporal biological heterogeneity within patient tumor samples and a lack of preclinical models that adequately reflect the entire biological spectrum. Novel lipid-based therapeutics that encompass ganglioside-directed immunotherapy, targeting lipid metabolism and membrane lipid therapy, have shown efficacy in the treatment of brain tumors but have yet to be evaluated in the treatment of ETMR. We carried out mass spectrometry imaging on ETMR patient samples to identify the histology-specific accumulation of lipids within the diverse cell populations of the tumor microenvironment. Our preliminary studies identified the accumulation of glycosphingolipids, cardiolipins, phosphatidylinositols, and ceramide-1-phosphates within tumor cells, including the characteristic multilayered rosettes, and within different microvascular proliferations. All data were correlated to histopathology and Ki67 proliferation index. We next evaluated the lipid profiles in the patient-derived ETMR cell line, BT183, compared to control neural stem cells (NSCs), grown as 3D tumorspheres and neurospheres, respectively. From this data we identified lipids that accumulated in our patient samples and the ETMR cell line but were significantly reduced or not detected in the control NSCs. Analysis aimed at a systems biology approach to study the ETMR microenvironment using imaging mass cytometry for multiplex IHC and spatial transcriptomics to correlate lipidomic phenotype to distinct cell populations within the microenvironment are ongoing. Preclinical model development based on these findings and drug screening of therapeutics targeting these lipidomic pathways are also ongoing.
LGG-12. CLINICAL AND MOLECULAR FEATURES OF DISSEMINATED PEDIATRIC LOW-GRADE GLIOMA
Authors: Adrian Levine, Cyril Li, Joseline Haizel-Cobbina, Liana Nobre, Julie Bennett, Michael Dewan, Uri Tabori, Cynthia Hawkins
Journal: Neuro-Oncology (2023)

Abstract Although most pediatric LGG (PLGG) have excellent long-term survival, there is a subset of cases that disseminate throughout the neuraxis (DLGG) that have very poor outcomes. The reason for this aggressive behavior is unknown but we hypothesize that distinct and specific biological mechanisms underlie the metastatic ability. The methylation-based class of diffuse leptomeningeal glioneuronal tumor (DLGNT) is characterized by MAPK pathway activating fusions with chromosome 1p loss, 19q loss, and/or 1q gain. However, it is unknown what proportion of DLGG match the DLGNT group, and which other methylations classes are at risk of metastasis. To improve our understanding of this rare patient population, we created an international DLGG consortium. Data from the first 68 cases shows a broad age distribution and no sex predilection. As expected, DLGG has much worse prognosis than the overall PLGG population. Virtually all DLGG progress at 5 years, compared to a quarter of other PLGG, and DLGG are 5-times more likely to die at 10 years. We observe three patterns of dissemination – 35% present with a localized mass and have secondary dissemination, 50% with disseminated tumor and a clear dominant mass, and 15% with disseminated disease without a dominant mass. In 47 patients with molecular testing, BRAF fusions accounted for 64% of driver alterations. Additional alterations were identified less frequently, including BRAF V600E (9%), FGFR1 alterations (9%), and KRAS mutations (4%). In 25 patients with methylation profiling, 10 (40%) successfully classified with a calibrated score above 0.8, illustrating that many cases do not fit a defined methylation group. The most common methylation classification was pilocytic astrocytoma (5 patients), and surprisingly only two patients classified as DLGNT. In sum this study illustrates the variable clinical behaviour associated with metastasis in PLGG and expands the range of molecular driver alterations, including ones previously unreported in DLGNT.
LGG-01. DEVELOPMENT OF A WEB-BASED CALCULATOR APPLICATION FOR PREDICTING SHORT- AND LONG-TERMSURVIVAL IN PEDIATRIC OPTIC PATHWAY GLIOMA: A POPULATION-BASED DATABASE ANALYSIS
Authors: Nolan Brown, Cathleen Kuo, Zach Pennington, Julian Gendreau, Drew Givens, David Daniels
Journal: Neuro-Oncology (2023)

Abstract Optic pathway gliomas (OPG) are generally low-grade lesions arising from the astrocytes of the visual pathway, most commonly of the optic nerves and chiasm. Uncertainty remains regarding the optimal management of this patient population. We sought to leverage population-level data from the Surveillance, Epidemiology, and End Results program database to develop a predictive calculator for overall survival (OS) amongst pediatric patients with OPG. A total of 1,052 patients who had been diagnosed with OPG were included. Multivariate cox proportional hazard model demonstrated patients of “other” race (hazard ratio [HR]=4.109, 95% confidence interval [CI] 1.076-15.694, p=0.039) exhibited a decreased overall survival, while patients with a median household income ≥$55,000 (HR=0.172, 95% CI 0.065-0.457, &amp;lt;0.001) and those who underwent subtotal resection (HR=3.549, 95% CI 1.092-13.364, p=0.047) had a higher overall survival rate. An online, interactive survival prediction tool (https://spine.shinyapps.io/optic_glioma/) was created to estimate 5-, 10-, and 15-year overall survival probability as well as median survival months. C-index was 0.722 (95% CI 0.642-0.776) for the training set and 0.745 (95% CI 0.661-0.790) for the validation set. Good concordance between the predicted probability and the actual probability of the dataset was also observed. This calculator may serve as a useful clinical tool during patient counseling. Further investigations aimed at developing calculators of visual acuity preservation and progression-free survival are merited; progress toward this end will benefit from continued multicenter collaborations.
EPEN-06. CHARACTERISING THE DEVELOPMENTAL ORIGINS AND TRAJECTORIES OF ZFTA-RELA FUSION EPENDYMOMA IN A NOVEL MOUSE MODEL
Authors: Sigourney Bonner, Claire King, Katherine Wickham Rarhmann, Elizabeth Cooper, Gunjan Katyal, Richard Gilbertson
Journal: Neuro-Oncology (2023)

Abstract Ependymomas driven by the ZFTA-RELA fusion account for &amp;gt;70% of all supratentorial ependymomas. These tumours are now recognised in the WHO classification of CNS tumours and have been associated with a poor prognosis. Seven ZFTA-RELA fusion variants have been described: around two thirds of cases are fusion 1. No spontaneous genetically modified mouse models (GEMMS) have been described and current models require invasive intracranial injection (of transduced cells or RCAS-TVA system). Here we describe the first spontaneous GEMM of ZFTA-RELA fusion-driven ependymoma. Nestin-Flx-STOP-Flx-ZFTA-RELA (Fusion 1) open reading frames were targeted together with luciferase to the Rosa-26 locus. Breeding these mice with Nestin-CreERT2 or Blbp-Cre lines that drive recombination in neural progenitor cells resulted in forebrain tumours that could be tracked with bioluminescence imaging from P20. Tumours displayed NF-kB and L1CAM expression and ZFTA-RELA protein was detected using a novel in-house antibody. Tumours display expression of a known ZFTA-RELA fusion ependymoma transcriptomic signature. ZFTA-RELA tumours can be grown as neurospheres and passaged as allografts in nude mice and respond to irradiation. We provide the first spontaneous GEMM of this important group of ependymomas. Here we present our histologic and transcriptomic developmental timecourse of these tumours, their comparison to the human disease and further understanding of the lineage origins and potential novel targets.
XRT-03. EFFICACY OF RE-IRRADIATION FOR PEDIATRIC DIFFUSE INTRINSIC PONTINE GLIOMAS
Authors: Linbo Cai, Mingyao Lai, Juan Li, Jiangfen Zhou, Shaoqun Li
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVE To analyze the efficacy and prognosticators of pediatric diffuse intrinsic pontine glioma (DPC) treated with re-irradiation. METHODS The clinical data and prognostic information of DIPG children younger than 18 years old who received re-irradiation in the Department of Oncology of Guangdong Sanjiu Brain Hospital from May 1, 2021, to November 1, 2022, were collected. The overall survival (OS) was calculated, and univariate analysis was performed to analyze the effect of tumor volume change and rate of change on survival. RESULTS Fifteen patients met the inclusion criteria. The median interval between the first and second radiotherapy was 8.8 months. The median survival after re-irradiation was 3.9 months, and the median overall survival was 16.9 months. Severe complications such as fatal radiation brain necrosis was observed after re-irradiation. CONCLUSIONS Re-irradiation is still the primary treatment for pediatric diffuse intrinsic pontine glioma, prolonging their survival.
HGG-08. COMBINATORIAL ACTIVITY OF CDK4/6-INHIBITORS AND TRAMETINIB IN PEDIATRIC HIGH-GRADE GLIOMA WITH BRAFV600E MUTATION AND HOMOZYGOUS CDKN2A DELETION
Authors: Lisa Mayr, Leah Mager, Lisa Gabler, Sibylle Madlener, Julia Berger, Dominik Kirchhofer, Anna Lämmerer, Katharina Bruckner, Daniela Lötsch, Walter Berger, Johannes Gojo
Journal: Neuro-Oncology (2023)

Abstract BRAFV600E mutations occur in 10-15% and homozygous CDKN2A deletions in approximately 40% of adolescent and pediatric high-grad glioma (HGG) and is associated with significantly decreased overall survival. Moreover, a subset of pHGG is defined by combined BRAFV600E mutation and concomitant CDKN2A homozygous deletion. Standard therapy has remained unchanged and consists of maximal safe resection and focal radiotherapy still resulting in poor overall survival. Therefore, new therapeutic approaches to increase patient survival are of utmost importance. Targeted therapy of BRAFV600E mutant HGG has emerged as effective treatment but remains challenging due to therapy resistance. CDK4/6 inhibitors represent a promising target in CDKN2A altered HGG. However, palbociclib demonstrated only low efficacy in HGG patients. Therefore, combination approaches may be more effective, and we investigated CDK4/6-inhibitors alone and in combination with trametinib in HGG cell models with BRAFV600E mutation and homozygous CDKN2A deletion. Efficacy of CDK4/6-inhibitor monotherapy and combinatorial approach with trametinib was assessed by short- and long-term viability assays in four patient-derived HGG cell models with homozygous CDKN2A deletion and BRAFV600E mutation. Furthermore, effects of CDK4/6 inhibitor therapy alone or in combination with trametinib on downstream signaling pathways (MAPK, PI3K) were analyzed with Western blots. Abemaciclib showed the highest activity in all cell models with IC50-values ranging from 0,5 – 2µM. Combined treatment approaches with trametinib showed synergistic effects across all cell models. Long-term viability assays revealed distinct sensitivity in the nanomolar range for CDK4/6-inhibitors and combined treatment with trametinib in all cell models. Exposure to abemaciclib and trametinib significantly decreased pRB, pERK, pS6, and pAKT protein expression levels when compared to monotherapy alone. Summarizing, combined treatment with CDK4/6-inhibitors and trametinib showed promising therapeutic effects on HGG models with homozygous CDKN2A deletion and BRAFV600E mutation. Currently, effects on cell cycle distribution and downstream molecular mechanisms are investigated to identify potential predictive biomarkers.
Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia
Authors: Miriam Ferrer, Nicholas Mourikis, Emma E. Davidson, Sam O. Kleeman, Marta Zaccaria, Jill Habel, Rachel Rubino, Qing Gao, Thomas R. Flint, Lisa Young, Claire M. Connell, Michael J. Lukey, Marcus D. Goncalves, Eileen P. White, Ashok R. Venkitaraman, Tobias Janowitz
Journal: Cell Metabolism (2023)
CNSC-04. EVALUATING LONGITUDINAL WORKING MEMORY PERFORMANCE IN PEDIATRIC PATIENTS WITH CRANIOPHARYNGIOMA VIA FMRI
Authors: Chih-Chiang Chang, Ping Zou, Matthew A Scoggins, Heather Conklin, Chia-Ho Hua, Thomas E Merchant, Ranganatha Sitaram
Journal: Neuro-Oncology (2023)

Abstract Craniopharyngioma is a type of benign brain tumor that develops in the suprasellar region of the brain and can lead to long-term neurological, endocrine, and visual impairments as well as neurocognitive deficits resulting from the tumor and its treatment. The contemporary treatment options for this tumor are radical surgery or limited surgery in conjunction with radiotherapy. The current understanding of the impact of brain injury related to the tumor and its treatment such as proton radiotherapy (PRT) on neurocognitive function is limited. The study (NCT01419067) was approved by the IRB and informed consent was obtained from patients or their parents. Functional magnetic resonance imaging (fMRI) was performed in a 3T MRI imaging system (Siemens MAGNETOM Prisma, Erlangen, Germany) and used to evaluate the neurocognitive performance of 58 pediatric patients (31 females and 27 males) before and after proton radiotherapy (PRT). The patients underwent serial imaging at four-time points (baseline, 18, 36, and 60 months after PRT) and performed a working memory (0-back, 1-back, and 2-back) task-based fMRI. A full factorial model was used for longitudinal group analysis at different time points through statistical parametric mapping. Omission errors, commission errors, and reaction time were measured for each task. The results showed robust detection of the working memory network with increased activation (FDR&amp;lt;0.05) in the precuneus, mid-temporal gyrus, and angular gyrus at 36 months compared to 18 months. The behavioral test results showed a gradual decrease in omission errors in the 2-back task group and an increase in reaction time for all three task groups over time. These findings suggest that PRT has a transient effect on brain activation and behavioral performance, potentially indicating improved executive functioning, recovery from the mass effect of the tumor and/or surgery, and the minimal negative impact from PRT.
LGG-13. GANGLIOGLIOMA DEEP TRANSCRIPTOMICS REVEALS A CD34+ PRIMITIVE NEUROECTODERM NEURAL PRECURSOR-LIKE POPULATION
Authors: Joshua Regal, Maria Guerra-Garcia, Vaibhav Jain, Vidyalakshmi Chandramohan, David Ashley, Simon Gregory, Eric Thompson, Giselle Lopez, Zachary Reitman
Journal: Neuro-Oncology (2023)

Abstract Gangliogliomas are glioneuronal brain tumors that typically present in childhood or early adulthood. Though most often low-grade, new insights are needed to refine glioneuronal tumor classification and to identify therapeutic approaches, particularly for unresectable, high-grade, and/or recurrent disease. Gangliogliomas often possess a rare population of immature astrocyte-appearing CD34+ cells. CD34 is expressed in neuroectoderm neural precursor cells during embryogenesis. Neural cell CD34 expression is usually lost prior to birth. We hypothesized that CD34+ ganglioglioma cells represent tumor precursor/stem cells and closely resemble ganglioglioma cells of origin. To test this, we evaluated five gangliogliomas with single nucleus RNA-seq, cellular indexing of transcriptomes and epitopes by sequencing, and/or spatially-resolved RNA-seq. Developmental trajectory analyses uncovered a neoplastic cellular hierarchy, with CD34+PAX6+SOX2+MSI1+PECAM1-VWF-DCN-COL1A2- cells being the most primordial and precursor to neuron-like and macroglia-like neoplastic cell states. Gene regulatory network inference of CD34+ ganglioglioma cells indicated TCF7L2/MEIS1-PAX6 and SOX2-mediated transcriptional programming, similar to that found during neuroectodermal/neural development in utero. Spatially-resolved transcriptomics revealed a neuroectoderm neural precursor-like tumor cell niche relatively devoid of vascular and immune cells. We used these high-resolution results to deconvolute clinically-annotated transcriptomic data, confirming that CD34+ neural precursor-like cell-associated gene programs associate with gangliogliomas compared to other brain tumors. Together, these deep transcriptomic approaches characterized a ganglioglioma cellular hierarchy - identifying CD34+ neuroectoderm neural precursor-like tumor-initiating cells, corresponding regulatory transcriptional programs, cell signaling pathways, and associated immune cell states. These findings may facilitate improved ganglioglioma tumor classification, diagnosis, and therapeutic investigations.
MDB-11. AN ONLINE CALCULATOR USING MACHINE LEARNING FOR PREDICTION OF SURVIVAL IN PEDIATRIC PATIENTS WITH MEDULLOBLASTOMA
Authors: Cathleen Kuo, Nolan Brown, Jaims Lim, Andre Monteiro, Matthew Recker, Moleca M Ghannam, Julian Gendreau, Veetai Li, Renée Reynolds
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVE Medulloblastoma is the most common malignant intracranial tumor affecting the pediatric population. Despite advancements in multimodal treatment over the past 2 decades yielding a &amp;gt;75% 5-year survival rate, children who survive often have substantial neurological and cognitive sequelae. The authors aimed to identify risk factors and develop a clinically friendly online calculator for prognostic estimation in pediatric medulloblastoma patients. METHODS Pediatric patients with a histopathologically confirmed medulloblastoma were extracted from the Surveillance Epidemiology and End Results database (2000-2019) and split into training and validation cohorts in an 80:20 ratio. The Cox proportional hazards model was used to identify the univariate and multivariate survival predictors. Subsequently, a calculator with those factors was developed to predict 2-, 5-, and 10-year overall survival as well as median survival months for pediatric medulloblastoma patients. The performance of the calculator was determined by discrimination, calibration, and decision curve analysis (DCA). RESULTS A total of 1,739 pediatric patients with medulloblastoma met the prespecified inclusion criteria. Fourteen variables, including age, sex, race, ethnicity, median household income, county attribute, laterality, histology, anatomical location, tumor grade, tumor size, surgery status, radiotherapy, and chemotherapy, were included in the calculator (https://spine.shinyapps.io/Peds_medullo/). The concordance index was 0.757 in the training cohort and 0.762 in the validation cohort, denoting clinically useful predictive accuracy. Good agreement between the predicted and observed outcomes was demonstrated by the calibration plots. The DCA curves indicated that the developed model has a good clinical prognostic benefit for pediatric medulloblastoma patients. CONCLUSION An easy-to-use prognostic calculator for a large cohort of pediatric patients with medulloblastoma was established. Future efforts should focus on improving granularity of population-based registries and externally validating the proposed calculator.
METB-03. THE DISTINCT GENOMICS OF HIGH-GRADE INFANT GLIOMAS AMONG PEDIATRIC GLIOMAS HARBORING RECEPTOR TYROSINE KINASE FUSIONS
Authors: Carlos A O de Biagi-Junior, Sebastian K Eder, Jenna LaBelle, Mariella G Filbin
Journal: Neuro-Oncology (2023)

Abstract Gliomas account for about 60% of pediatric brain tumors, about half of which are classified as high-grade. Recent studies have shown that infants with high-grade gliomas (HGG) harboring receptor tyrosine kinase (RTK) fusions have a more favorable prognosis than pediatric HGG patients. The molecular mechanisms for this favorable, but from the histology divergent clinical outcome, are yet unknown. We analyzed n=18 brain tumor samples (n=7 infant, n=11 pediatric) of patients with low-grade glioma (LGGs) or HGG presenting with RTK fusions using single-cell RNA sequencing. Considering the different fusion genes (ALK n=6, NTRK n=8, and MET n=4), age groups, and glioma grades, we evaluated the metaprograms of tumor cells and their proportions using non-negative matrix factorization. Preliminary results show similar metaprograms comparing infant and pediatric LGG. Cells detected as MES-like did not occur in LGG but were found in several HGG samples. However, in HGG, the MES-like cells show different expression patterns for infant and pediatric samples. In addition, compared with pediatric HGG, infant HGG has a higher proportion of programs that are predominantly present in LGG, such as AC-like and NPC-like. These initial findings serve as a starting point for cell type-specific transcription factor regulatory networks and are an important step toward understanding the underlying biology of this distinct pediatric brain tumor entity.
OUTC-06. BEST PRACTICES FOR THE SUCCESSFUL ADMINISTRATION OF COMBINATION METRONOMIC ANTI-ANGIOGENIC AND INTRAVENTRICULAR THERAPY
Authors: Kasey L Burnside, Ashley S Margol, Katrina O’Halloran, Nathan J Robison, Teresa Rushing, Tom B Davidson, Kasey Rangan, Kaaren Waters
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Combination metronomic anti-angiogenic and intraventricular therapy incorporates a customized administration of a five-drug oral antiangiogenic regimen with intravenous bevacizumab and intraventricular chemotherapy and is an effective treatment regimen for children with recurrent central nervous system embryonal tumors. This treatment can be administered while maintaining quality of life and avoiding severe side effects through personalized therapy schedules; however, dosing modifications, available dosage formulations, and complexity of medication administration creates challenges for families and clinical staff. METHODS A retrospective chart review was completed on 11 patients who received this treatment with various combinations of oral medications (thalidomide, etoposide, cyclophosphamide, celecoxib, and fenofibrate), intravenous (IV) medication (bevacizumab), and intraventricular chemotherapy (cytarabine, etoposide, and topotecan). We implemented successful nursing interventions, family education, variable scheduling options, dosage formulation selections, and innovative oral and intraventricular administration techniques. RESULTS Patients were able to successfully receive therapy for an average of 14 months and no patient came off for toxicity. Treatment was generally well-tolerated, with most toxicities being hematologic or gastrointestinal in nature. CONCLUSION Education, innovative dosing schedules, recognition of potential side effects, and medication administration allow for successful administration of this complex therapy.